The place of polypill in secondary prevention of stroke
Authors: Dike B Ojji, Mark D Huffman
Journal: The Lancet Global Health (2023)

People who have had a stroke are confronted with multiple medications and complex treatment regimens, both associated with low adherence. As a result of barriers at the health system, health-care professional, and patient levels, most people around the world who have had a stroke or heart attack do not take any medications to prevent a recurrent event.1Zhu JZ Manne-Goehler J Agarwal A et al.Medication use for cardiovascular disease prevention in 40 low- and middle-income countries.J Am Coll Cardiol. 2023; 81: 620-622Crossref PubMed Scopus (3) Google Scholar Unfortunately, this prevention gap has not narrowed in the past decade. Fixed-dose combination therapy was proposed as a strategy to improve secondary prevention treatment rates in 2001.2WHOSecondary prevention of noncommunicable diseases in low- and middle-income countries through community based and health service interventions: World Health Organization Wellcome Trust meeting report, 1–3 August 2001.https://apps.who.int/iris/handle/10665/42567Date: August 2001Date accessed: July 28, 2023Google Scholar A 2003 meta-analysis considered the advantages of this as a mass prevention strategy, using medical history and age to identify individuals who might benefit from fixed-dose combinations that include antiplatelet, lipid lowering, and blood pressure lowering drugs. It introduced the term polypill for the daily combination therapy of drugs from multiple classes.3Wald NJ Law MR A strategy to reduce cardiovascular disease by more than 80%.BMJ. 2003; 3261419Crossref Google Scholar This approach led to substantial debate over which patients would benefit, what combinations and comparator groups should be used, and would polypills lead to over-medicalisation? Thus, the initial promise and enthusiasm for polypills waned. However, based on over two decades of research demonstrating their benefits, WHO added polypills to its list of essential medicines in July 2023.4WHOWHO Model List of Essential Medicines–23rd list, 2023.https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2023.02Date: Jul 26, 2023Date accessed: August 28, 2023Google Scholar It is in this context that the publication of Fred Stephen Sarfo and colleagues’ SMAART trial in The Lancet Global Health5Sarfo FS Voeks J Adamu S et al.A cardiovascular polypill for secondary stroke prevention in a tertiary centre in Ghana (SMAART): a phase 2 randomised clinical trial.Lancet Global Health. 2023; 11: e1619-e1628Google Scholar is important and timely. In this phase 2 randomised controlled trial the authors evaluated the efficacy and safety of two Polycap pills (Cadila Pharmaceuticals, Ahmedabad, India) taken daily (each containing 5 mg ramipril, 50 mg atenolol, 12·5 mg hydrochlorothiazide, 20 mg simvastatin, and 100 mg aspirin) compared with usual care among 148 patients (mean age=58·5 years, 50% female and 50% male) with a recent ischaemic stroke in a tertiary medical centre in Ghana. The primary outcome was between group difference change in carotid intimal media thickness (CIMT), a pre-clinical surrogate marker of cardiovascular disease, at 12 months. Among the 123 (83%) of 148 patients with follow-up data, mean change in CIMT at month 12 from baseline was –0·017 mm (95% CI –0·067 to 0·034) in the polypill arm versus –0·092 mm (–0·130 to –0·051) in the usual care arm, with an adjusted mean difference of 0·049 mm (–0·008 to –0·109; p=0·105). Serious adverse events occurred in eight (11%) participants on the polypill versus two (3%) participants in the usual care group. There were no significant differences in secondary outcomes, including unadjusted risk factor levels, medication adherence, or health-related quality of life between the two groups. First, these data should be placed into the broader context of polypill research, which includes 26 previous trials and 27 317 participants in primary and secondary prevention populations across a wide range of countries, which supported WHO's decision to include the polypill in its essential medicine list. Notably, the Secondary Prevention of Cardiovascular Disease in the Elderly (SECURE) trial is the only sufficiently powered secondary prevention study published to date. It showed a 24% relative risk reduction (hazard ratio [HR] 0·76, 95% CI 0·60–0·96) over a median follow-up of 36 months between the polypill (100 mg aspirin; 2·5 mg, 5 mg, or 10 mg ramipril; and 20 mg or 40 mg atorvastatin) group and usual care group in a well-treated secondary prevention population in Europe.6Castellano JM Pocock SJ Bhatt DL et al.Polypill strategy in secondary cardiovascular prevention.N Engl J Med. 2022; 387: 967-977Crossref PubMed Scopus (63) Google Scholar A 2021 meta-analysis from large (studies with >1000 participants and >2 years follow-up) polypill trials with primary and secondary prevention populations demonstrated even larger benefits (0·62, 0·53–0·73) with a similar direction and magnitude of effect between these prevention groups.7Joseph P Roshandel G Gao P et al.Fixed-dose combination therapies with and without aspirin for primary prevention of cardiovascular disease: an individual participant data meta-analysis.Lancet. 2021; 398: 1133-1146Summary Full Text Full Text PDF PubMed Google Scholar Reasons for the differences between these data and the results reported by Sarfo and colleagues probably relate to their relatively small sample size (148 participants), high baseline treatment rates associated with tertiary care settings, moderate attrition rates, a shorter follow-up period, and challenges in reliably measuring CIMT. Second, these results should encourage investigators to pursue further polypill research, especially large-scale collaborative implementation trials in settings where polypill research has been scarce, such as Ghana and other countries in sub-Saharan Africa. Co-interventions and multilevel implementation strategies that provide risk protection and reduce patients’ out-of-pocket expenses will be needed to maximise feasibility, acceptability, affordability, and effectiveness. Polypills are not a panacea, but they are a pragmatic, scalable, and cost-effective strategy to help prevent fatal and non-fatal cardiovascular disease events, especially in people at high risk or with low treatment rates. The investigators of the SMAART trial should be applauded for helping to close an important research gap by conducting a polypill trial in sub-Saharan Africa, where previous polypill research has been scarce. The trial was also conducted during the COVID-19 pandemic, a global challenge all unto itself. Much has been learned over the past 20 years to advance the science of polypills, and the results of the trial by Sarfo and colleagues remind us that the journey continues. MDH has received travel support from the American Heart Association and World Heart Federation and holds an appointment at The George Institute for Global Health, which has a patent, license, and has received investment funding with intent to commercialise, fixed-dose combination therapy through its social enterprise business, George Medicines. MDH has pending patents for heart failure polypills. DBO declares no competing interests. A cardiovascular polypill for secondary stroke prevention in a tertiary centre in Ghana (SMAART): a phase 2 randomised clinical trialThe polypill regimen resulted in similar regression in subclinical atherosclerosis and many secondary and tertiary outcome measures as the tailored drug regimen, but with more serious adverse events. Larger, longer-term, event-based studies, including patients with stroke in primary care settings, are warranted. Full-Text PDF Open Access